{67 -methylene-1-cyclopentene-1-pentanoic acid

ABSTRACT

Dieneoic acid delta -methylene-1-cyclopentene-1-pentanoic acid is obtained by reacting cyclopentanone with one chemical equivalent of methylsulfinylmethide alkali metal salt in dimethyl sulfoxide. Lithium aluminum hydride reduction of the acid provides Epsilon -methylene-1-cyclopentene-1-pentanol. The acid, metal salts thereof, lower alkyl esters, and the alcohol are effective antifungal agents.

United States Patent Comer et al.

[ Dec 10, 1974 B-METHYLENE-l-CYCLOPENTENE-l- PENTANOIC ACID Inventors: William T. Comer; James W.

Rayburn; Davis L. Temple, all of Evansville, Ind.

Assignee: Mead Johnson & Company,

Evansville, Ind.

Filed: Oct. 26, 1972 Appl. No.2 300,942

Related US. Application Data Continuation-in-part of Ser. No. 246,309, April 21, 1972, abandoned.

U.S. Cl. 260/468 L, 260/4299, 260/438.1, 260/448 R, 260/514 L, 260/617 R, 424/305, 424/317, 424/343 Int. Cl. C07c 61/26, C070 69/74 Field of Search 260/468 L, 514 L, 514 CA [56] References Cited OTHER PUBLICATIONS French et al. TACS, 71, 3702 (1949).

Primary Examiner-Robert Gerstl Attorney, Agent, or Firm-Robert H. Uloth; Robert E. Carnahan [5 7 ABSTRACT 11 Claims, N0 Drawings -MEJHXLM- r CL E TENETI' PENTANOIC ACID CROSS-REFERENCE TO RELATED APPLICATIONS BACKGROUND OF THE INVENTION This invention is concerned with carbon compounds and in particular olefinic carboxylic acids and a process for making same. It is further concerned with alkyl ester derivatives of the olefinic acids and alkali metal salts thereof.

The compounds of the present invention are antifungal agents.

SUMMARY OF THE INVENTION In the above formulas, R signifies hydrogen or methyl with the proviso that whenever R is methyl the R' cyclopentenyl radical is selected from the group consisting of 3-methyl-l-cyclopentenyl and 4-methyll-cyclopentenyl; and R represents hydrogen or lower alkyl. By the term lower alkyl" it is meant that the carbon chains which comprise this group include both straight and branch chain carbon radicals of from 1 to 4 carbon radicals of from 1 to 4 carbon atoms inclusive such as methyl, ethyl, propyl, isopropyl, l-butyl, lmethylpropyl, 2-methylpropyl, and tert'.-butyl.

It will be apparent to those skilled in the art that both geometrical and optical stereoisomeric forms of the compounds of Formula I wherein R is methyl are possible, and it is to be understood that this invention comprehends all forms thereof.

Diene acids of Formula I wherein R is hydrogen and R is as above are obtained in accord with theprocess of the present invention by reacting a member of the group consisting of cyclopentanone, 3-methylcyclopentanone, and 2-cyclopentylidene cyclopentanone, with one chemical equivalent of a methylsulfinylmethide alkali metal salt such as sodium methylsulfinylmethide, potassium methylsulfinylmethide or liththe carboxylic acid alkali metal salt. The carboxylic acid is isolated by dissolving the salt in water, neutralizing with acid, and extracting with an organic solvent such as ether. Evaporation of the solvent provides the acid which is purified by conventional techniques such as distillation and crystallization.

The fact that the diene acids of the present invention are obtained according to the above method by reaction of a cyclopentanone or the 2-cyclopentylidene cyclopentanone products with methylsulfinyl carbanion in dimethylsulfoxide is surprising and highly unexpected. For instance, E. J. Corey, et al., J. Am. Chem. Soc., 84, 866 (1962), 87, 1345 (1965), report that under similar conditions cyclohexanone and cycloheptanone yield only corresponding enolate anions or beta-hydroxysulfoxide products. The reaction of methylsulfinyl carbanion with a cycloalkyl ketone in dimethylsulfoxide to provide diene carboxylic acids is believed to be quite specific in nature and limited to cyclopentanone and its 3-alkyl vsubstituent. Reaction of 2-methylcyclopentanone with dimethylsulfoxide provides the corresponding dienoic acid in trace amounts. Cycloalkyl ketones such as cyclobutanone, 2,5-dimethylcyclopentanone, and 3,4-dimethylcyclopentanone do not give diene carboxylic acids analogous to those of Formula I under the conditions of the procedure described herein.

Alkali metal salts of the diene carboxylic acids of Formula I can be obtained directly by utilizing the appropriate alkali metal methylsulfinyl carbanion. Other acting the diene carboxylic acid with an excess of the alcohol in ether solvent employing a catalytic amount of perchloric acid at 25C.

Reduction of the dienoic acids with lithium aluminum hydride provides the corresponding alcohols of Formula II.

The compounds of Formulas l and [I possess good antifungal properties which can be readily demonstrated by the disc-plate method. According to this well-known method, Sabouraud dextrose agar is inoculated with suspensions of various pathogenic dermatophytes and related fungi and the inoculated agar allowed to solidify in sterile petri dishes. A solution of the test agent is added to filter paper discs and the discs placed on the agar surface of the plate. The plates are then incubated at 30C. and zones of inhibition are measured for various drug concentrations and compared with standard reference agents such as undecylinic acid. The lowest culture is determined by varying the drug concentration and is designated as the minimal inhibitory concentration (MIC). The following table is illustrative of the MIC values obtained for S-methylene-l-cyclopentene-l-pentanoic acid and the ethyl ester thereof compared to undecylenic acid.

TABLEI IN VITRO ANTIFUNGAL ACTIVITY Minimum inhibitory Undecylenic Acid Concentration (meg/ml.)

S-Methylenel -cyclopentenel -pentanoic Agid Microsporum audouini ATCC 9079 25 Microsporum canis ATCC 1024i 25 Trichophyton mentagrophytes 25 (gypseum) ATCC 9129 Trichophyton rnentagrophytes 25 (interdigitale) ATCC 9972 Trichophyton mentagrophytes 25 (asteroides) ATCC 8757 Candida albicans ATCC 1023] Ethyl vS-methylene-l-cyglopgntgne-lgentanoate Microsporum audouini ATCC 9079 25 Microsporum canis ATCC 10241 50 Trichophyton mentagrophytes 25 (gypseum) ATCC 9129 Trichophyton mentagrophytes 50 (interdigitale) ATCC 9972 Trichophyton mentagrophytes 25 (asteroides) ATCC 8757 Candida albicans ATCC 10231 100 The compounds of the present invention. are relatively non-toxic compounds. in mice, for instance, 6-methylene-l-cyclopentene-l-pentanoic acid and ethyl fi-methylene-l-cyclopentene-l-pentanoate have an ALD of greater than 2,000 mg./kg. body weight upon oral administration.

The following examples are given by way of illustration and are not be construed as limitations of this invention.

EXAMPLE 1 v E-methylene-l -cyclopenten'el -pentanoic acid Sodium methylsulfinyl carbanion is prepared under nitrogen by adding a 57% mineral oil dispersion of sodium hydride (54.0 g., 1.28 mole) to 250 ml. of dry dimethyl sulfoxide with stirring and then slowly. increas ing the temperature of the suspension to 7lC. where it is maintained until hydrogen is no longer evolved. The gray mixture of sodium methylsulfinyl carbanion is then immediately cooledt-o 25C. and cyclopentanone (100.0 g., 1.19 mole) added dropwise thereto. The reaction of cyclopentanone with the carbanion is slightly exothermic and is moderated in an ice bath for 0.5 hr. The reactionmixture is stirred at 25C. for an additional hr. period, poured into 2 l. of chilled 1:1 methylene chloride-ether in an ice bath, refrigerated overnight, and the finely divided precipitated product iscollected and washed with 9:1 ether-methylene chloride. Air drying provides 197 g. of the sodium salt of 8-methylene-l-cyclopentene-l-pentanoic acid (62.8 g., 59%) as an orange oil which solidifies on standing. Purification of the acid is carried out by conversion to its sodium salt, followed by neutralization to provide analytically pure d-methylene-l-cyclopentenel -pentanoic acid as white crystals M.P. 43.5-56.5C. (corr. iiltraviolet absorption spectrum in ethanol exhibits a single band at 237 nm (c max 16,300).

Analysis. Calcd. (percent for C.,H,.,0,= C, 73.30; H, 8.95. Found (percent): C, 73.20; H, 8.83. NMR 8 (ppm) (CDCl ,.tetramethylsilane ref.): 1.88 [m, 6H, (CH 2.38 [m,6H, (CH-2C=)3], 4.98 (s, 2H, =CH 5.87 (s, 1H, =CH), 9.l2(s, 1H, CO H).

infrared (pelleted with K Br): 1720 cm. (C=O), 1620 cm. (C=C), 1580 cm. (C=C).

EXAMPLE 2 Ethyl 'd-methylenel -cyclopentene-l -pentanoate N,N-Carbonyldiimidazole .(11.3 g., 0.07 mole) is added in small portions to iS-methylene-l-cyclopentene-l-pentanoic acid (11.6 g., 0.065 mole) in ml. dry tetrahydrofuran. After carbon dioxide evolution has ceased, 50 ml. of absolute ethanol containing a catalytic amount of sodium ethoxide is added, the mixture stirred at room temperature for 2 hr. and then most of the solvent evaporated under reduced pressure. The residue thus obtained is dissolved in ether, washed with water, and cold solutions of l N. NaOH and l N. HCl. Drying the ethereal extract over a magnesium sulfate and evaporating in vacuo provides 13.5 g. (100%) of the ester as a yellow oil. Distillation of the yellow oil yields analytically pure ethyl S-methylene-lcyclopentene-l-pentanoate as a pale yellow oil having a'boiling point of 71C. at 0.2 mmHg n 1.484; infrared film exhibits carbonyl absorption at 1740 cm..

Analysis. Calcd. (percent) for C H O C, 74.96; H, 9.68. Found (percent): C, 74.88; H, 9.77.

NMR 6 (ppm) (CDC1;,, tetramethylsilane ref), 1.24 (t, 3H, CH l.88 [m, 6H, (CH 2.38 [m, 6H, (CH 4.13 (q, 2H, CH CH 4.98 (s, 2H, =CH

+5.87 s, ll-L CH).

w-Infrared (film): 1730 cm." (C=O), 1620 cm.

n -butyl S-methylenel -cyclopentenel -pentanoate, tert.-butyl fi-methylenel -cyclopentenel pentanoate.

EXAMPLE 3 V Reaction of 3-methylcyclopentanone with sodium methylsulfinyl carbanion By substituting an equimolar weight of 3-methylcyclopentanone in the procedure of Example 1 for cyclopentanone, there is'produced an isomeric mixture of o-methylene-l-cyclopentene-l-pentanoate along with a substantial amount of 3-methylglutaric acid. Esterification of this mixture of acids according to the procedure of Example 2 produces the corresponding ethyl esters. Purification is carried out by fractional distillation through a 6 inch Vigreaux column to provide first the side-product diethyl S-methylglutarate, b.p. 82C. at 0.2 mm Hg., and then the ester fraction having a boiling point of l 16C. at 0.3 mm Hg., n 1.3074. According to vapor phase chromatographic analysis and nmr spectral data, the ester product consists of an equal mixture of both isomers of ethyl ,B-methyl-S- methylene-l-(3-methylcyclopentene)-l-pentanoate and ethyl ,B-methyl8-methylenel 4- methylcyclopentene)-l-pentanoate illustrated by Formula Ill and Formula [V respectively.

Analysis. Calcd. for C H O (percent): C, 76.22; H, 10.24. Found (percent): C, 76.20; H, 10.20.

EXAMPLE 4 Reaction of 2-cyclopentylidene cyclopentanone with sodium methylsulfinyl carbanion 2-Cyclopenty1idene cyclopentanone (6.4 g., 0.043 mole) obtained according to the method of French, et al., J. Am. Chem. Soc., 71, 3702 (1949) is added in the manner of the procedure of Example 1 to sodium methylsulfinyl carbanion obtained from 1.94 g. of a 53% mineral oil dispersion of sodium hydride in dimethyl sulfoxide. There is thus obtained 5.6 g.,- of the sodium salt of S-methylene-l-cyclopentene-l-pentanoic acid which, if desired, can further be neutralized to provide the free acid in a 26 percent yield.

By substitution of 2-cyclopentylidene cyclopentanone in the above procedure with an equimolar weight of 2(3-methylcyclopentylidene)-3-methylcyclopentanone there is produced B-methyl-vS-methylene-l-(3- methylcyclopentene)-l-pentanoic acid and B-methyla-methylene-l-(4-methylcyclopentene)-1-pentanoic acid.

EXAMPLE 5 e-Me'thylenel -cyclopentenel -pentanol S-Methylene-l-cyclopentene-l-pentanoic acid (60.3 1

tered. The filtrate dried over magnesium sulfate and concentrated under reduced pressure provides 50.9 g. (91 percent yield) of pure product according to nmr data. The product can be distilled with considerable polymerization, and has a boiling point of 82C. at 0.1

, mm Hg.

Analysis. Calcd. for C H O (percent): C, 79,46; H, 10.91. Found (percent): C, 79.30; H, 10.96.

NMR 8 (ppm) (CDCl tetramethylsilane ref.): 5.77 (s, 1H, =CH); 4.90 (S, 2H, =CH 3.63 (t, 2H, CH OH).

The in vitro antifungal activity of e-methylene-lcyclopentene-l-pentanol by the disc-plate method is as follows:

Minimum Inhibitory Test Organism Concentration (mcg./ml.)

Microsporum audouini ATCC 9079 50 Microsporum canis ATCC 10241 50 Trichophyton mentagrophytes 50 (gypseum) ATCC 9129 Trichophyton mentagrophytes 5O (interdigitale) ATCC 9972 Trichophyton mentagrophytes 50 (asteroides) ATCC 8757 Candida albicans ATCC 10231 FORMULA I wherein R is hydrogen or methyl with the proviso that whenever R is methyl the il -cyclopentenyl radical is selected from the group consisting of 3-methyl-lcyclopentenyl and 3-methyl-l-cyclopentenyl;

R is hydrogen, lower alkyl; or whenever R is hydrogen the non-toxic pharmaceutically acceptacle metal salts thereof.

2. The compound according to claim 1 which is 6-methylene-l-cyclopentene-l-pentanoic acid.

3. The sodium salt of the compound of claim 2. 4. The compound according to claim 1 which is ethyl S-methylenel -cyclopentenel -pentanoate.

5. The compound according to claim 1 which is B-methyl-S-methylenel 3-methylcyclopentene l pentanoic acid.

6. The compound according to claim 1 which is ethyl B-methyl.-8-methylenel 3-methylcyclopentene l pentanoate.

7. The compound according to claim 1 which is [3-methyl-6-methylene l-(4-methylcyclopentene)-1- pentanoic acid.

8. The compound according to claim 1 which is ethyl B-methyl-S-methylenel 4-methylcyclopentene l pentanoate;

9. The process for the preparation of diene carboxylic acids claimed in claim 1 wherein R is hydrogen or methyl and R is hydrogen which comprises reacting a member of the group consisting of cyclopentanone,

3-methylcyclopentanone, and Z-cyclopentylidene cyclopentanone, with one chemical equivalent of a meacid. 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF DIENE CARBOXYLIC ACIDS AND ESTERS OF FORMULA 1
 2. The compound according to claim 1 which is delta -methylene-1-cyclopentene-1-pentanoic acid.
 3. The sodium salt of the compound of claim
 2. 4. The compound according to claim 1 which is ethyl delta -methylene-1-cyclopentene-1-pentanoate.
 5. The compound according to claim 1 which is Beta -methyl-delta -methylene-1-(3-methylcyclopentene)-1-pentanoic acid.
 6. The compound according to claim 1 which is ethyl Beta -methyl- delta -methylene-1-(3-methylcyclopentene)-1-pentanoate.
 7. The compound according to claim 1 which is Beta -methyl-delta -methylene-1-(4-methylcyclopentene)-1-pentanoic acid.
 8. The compound according to claim 1 which is ethyl Beta -methyl- delta -methylene-1-(4-methylcyclopentene)-1-pentanoate.
 9. The process for the preparation of diene carboxylic acids claimed in claim 1 wherein R1 is hydrogen or methyl and R2 is hydrogen which comprises reacting a member of the group consisting of cyclopentanone, 3-methylcyclopentanone, and 2-cyclopentylidene cyclopentanone, with one chemical equivalent of a methylsulfinylmethide alkali metal salt in dimethyl sulfoxide at 0*-25*C. to provide the diene carboxylic acid alkali metal salt; and thereafter neutralizing said salt with acid.
 10. The process for the preparation of the sodium salt of delta -methylene-1-cyclopentene-1-pentanoic acid according to claim 9 wherein cyclopentanone is reacted with sodium methylsulfinylmethide.
 11. The process for the preparation of delta -methylene-1-cyclopentene-1-pentanoic acid according to claim 10 wherein the sodium salt of 5-cyclopentylidene-4-methylenevaleric acid is neutralized with hydrochloric acid. 